The present invention relates to three-dimensional structures' of hematopoietic prostaglandin D synthase (which may refer to as “PGDS” hereinafter), and a method for designing PGDS inhibitor using the three-dimensional structures.
Prostaglandin D2 (PGD2) is synthesized in vivo by PGDS from prostaglandin H2 (PGH2). There are two types of PGDS, i.e., brain-type PGDS and hematopoietic PGDS. Hematopoietic PGDS absolutely requires glutathione for enzymatic reactions while brain-type PGDS also causes enzymatic reactions in the presence of thiol reagents other than glutathione.
PGD2 is synthesized in the central nervous system by brain-type PGDS, and has functions of sleep induction, thermodepression, inhibition of secretion of corpus luteum hormone and control of responses to pain and odor. PGD2 is synthesized in peripheral tissue by hematopoietic PGDS, and is known to have physiological functions including dilation of peripheral blood vessels, bronchoconstruction, and inhibition of platelet coagulation. It also acts as an allergic mediator released from mast cells (Lewis, R. A., Soter, N. A., Diamond, P. T., Austen, K. F., Oates, J. A. & Roberts, L. J. Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE. J. Immunol., 129, 1627-1631 (1982)). It has been reported that allergic reaction is significantly reduced in knockout mouse lacking prostaglandin D2 receptor protein (DP receptor) (Matsuoka, T., Hirata, M., Tanaka, H., Takahashi, Y., Murata, T., Kabashima, K., Sugimito, Y., Kobayashi, T., Ushikubi, F., Aze, Y., Yoshida, N., Honda, Y., Nagai, H. & Narumiya, S. Prostaglandin D2 as a mediator of allergic asthma. Science, 287, 2013-2017 (2000)). There is another prostaglandin D2 receptor (CRTH receptor) in Th2 lymphocytes, eosinophils, and basophils involved in allergic reactions, which promotes chemotaxis of those inflammatory cells (Hirai, H., Tanaka, K., Yoshie, O., Ogawa, K., Kenmotsu, K., Takamori, Y., Ichimasa, M., Sugamura, K., Nakamura, M., Takano, S., and Nagata, K., Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils and basophils via seven-transmembrane receptor CRTH2, J. Exp. Med., 193, 255-261 (2001)). The synthesis of prostaglandin D2 in mast cells (Urade, Y., Ujihara, M., Horiguchi, Y., Igarashi, M., Nagata, A., Ikai, K. and Hayaishi, O. Mast cells contain spleen-type prostaglandin D synthase, J. Biol. Chem., 265, 371-375 (1990)) and human Th2 lymphocytes (Tanaka, K., Ogawa, K., Sugamura, K., Nakamura, M., Takano, S, and Nagata, K., Differential production of prostaglandin D2 by human helper T cell subsets, J. Immunol., 164, 2277-2280 (2000)) is made by hematopoietic PGDS.
If a compound capable of inhibiting the enzymatic activity of PGDS is discovered, it would become possible to control PGD2 synthesis to obtain anti-allergic agents, sleep control agents and anti-obesity agents.
Recently, attempts to design medicines from the three dimensional structure of proteins have been made. However, no one has succeeded in determining the three dimensional structure of human hematopoietic PGDS. It is hence difficult to design an inhibitor of human hematopoietic PGDS from the three dimensional structure thereof. It is an object of the present invention to clarify the three dimensional structure of human hematopoietic PGDS to provide a method for designing an inhibitor of human hematopoietic PGDS using the three dimensional structure.